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SECTION II Drug Dosage Form and Drug Delivery System Design

Table 4.2 EXAMPLE PROTOCOL FOR DRUG AND/OR DRUG PRODUCT STABILITY
STUDIESa
Study Type

Storage Condition

Minimum Time Period

Long term

25C2C @ 60% RHb5% RH

12 mo

Intermediate

30C2C @ 65% RH 5% RH

6 mo

Accelerated

40C2C @ 75% RHa5% RH

6 mo

For chemical entities. Adapted from Stability and Testing of New Drug Substances and Products. Available at: http://
www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128204.pdf. (Accessed September 28, 2012).
b
RH, relative humidity.
a

on at least three batches of the manufactured

dosage form, packaged in the container and
closure system, including all secondary packaging (e.g., outer carton) proposed for marketing. The studies should include testing of
those attributes of the product that are susceptible to change during storage, thereby affecting quality and efficacy. The testing should
cover, as appropriate, the physical, chemical,
biological, and microbiological attributes;
preservative content (e.g., antioxidant, antimicrobial preservative); and functionality
tests (e.g., metered-dose delivery system).

Table 4.2 presents an example protocol

for long-term, intermediate, and accelerated
stability studies for a chemical drug entity
and dosage form product. Protocols vary for
products intended to be maintained under
conditions of refrigeration, for those to be
frozen, for products known to be destined for
geographic areas of temperature extremes,
and for biotechnological/biological products, which have separate protocols for stability studies. Physical Pharmacy Capsule
4.19 presents the Q10 Method of Shelf Life
Estimation.

Physical Pharmacy Capsule 4.19

Q10 Method of Shelf Life Estimation

The Q10 approach, based on Ea, which is independent of reaction order, is described as
Q10 = e{

(Ea/R ) (1/ T +10) (1/ T )}

where
Ea is the energy of activation,
R is the gas constant, and
T is the absolute temperature.
In usable terms, Q10, the ratio of two different reaction rate constants, is defined thus:
Q10 =

K ( T +10)
KT

The commonly used Q values of 2, 3, and 4 relate to the energies of activations of the reactions
for temperatures around room temperature (25C). For example, a Q value of 2 corresponds
to an Ea (kcal/mol) of 12.2, a Q value of 3 corresponds to an Ea of 19.4, and a Q value of 4
corresponds to an Ea of 24.5. Reasonable estimates can often be made using the value of 3.

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Chapter 4 Pharmaceutical and Formulation Considerations

149

Physical Pharmacy Capsule 4.19 cont.

The equation for Q10 shelf life estimates is
t 90 ( T2 ) =

t 90 ( T1)

( T /10)
Q10

where
t90T2 is the estimated shelf life,
t90T1 is the given shelf life at a given temperature, and
T is the difference in the temperatures T1 and T2.
As is evident from this relationship, an increase in T will decrease the shelf life and a decrease in T will increase the shelf life. This is the same as saying that storing at a warmer temperature will shorten the life of the drug and storing at a cooler temperature will increase the
life of the drug.

Example 1
An antibiotic solution has a shelf life of 48 hours in the refrigerator (5C). What is its estimated
shelf life at room temperature (25C)?
Using a Q value of 3, we set up the relationship as follows:
t 90 ( T2 ) =

t 90 ( T1)

( T /10)

Q10

48
3

(25 5)/10

48
= 5.33 hours
32

Example 2
An ophthalmic solution has a shelf life of 6 hours at room temperature (25C). What is the estimated shelf life in a refrigerator at 5C? (Note: Since the temperature is decreasing, T will be
negative.)
t 90 ( T2 ) =

6
3

( 5 25)/10

6
= 6 32 = 54 hours
32

These are estimates, and actual energies of activation can often be obtained from the literature for more exact calculations.

Following FDA product approval and initial marketing, pharmaceutical manufacturers retain production samples of drug/drug
product for 5 years or longer and continue
studies for signs of degradation under various conditions of storage. Pharmacy practitioners should also observe signs of product
instability (e.g., color change, distorted capsules, softened tablets, etc.) and report such
findings.
Prescriptions requiring extemporaneous compounding by the pharmacist do
not require the extended shelf life that

0002035883.INDD 149

commercially manufactured and distributed

products do because they are intended to be
used immediately on receipt by the patient
and used only during the immediate course
of the prescribed treatment. However, these
compounded prescriptions must remain
stable and efficacious during the course of
use, and the compounding pharmacist must
employ formulative components and techniques that will result in a stable product (7).
Today, there are a number of literature sources for the pharmacist to utilize
in the compounding of high quality and

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